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Continued Caution Recommended in Use of Intravenous Iron Preparations

  • Author Footnotes
    ∗ On behalf of the Cochrane Adverse Effects Methods Group
    Francois Cachat
    Footnotes
    ∗ On behalf of the Cochrane Adverse Effects Methods Group
    Affiliations
    University Hospital of Bern, Switzerland
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  • Author Footnotes
    ∗ On behalf of the Cochrane Adverse Effects Methods Group
    Su Golder
    Footnotes
    ∗ On behalf of the Cochrane Adverse Effects Methods Group
    Affiliations
    Department of Health Sciences, University of York, UK
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  • Author Footnotes
    ∗ On behalf of the Cochrane Adverse Effects Methods Group
    Daniela R. Junqueira
    Footnotes
    ∗ On behalf of the Cochrane Adverse Effects Methods Group
    Affiliations
    Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
    University of Sydney, Sydney, Australia
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  • Author Footnotes
    ∗ On behalf of the Cochrane Adverse Effects Methods Group
    Sunita Vohra
    Footnotes
    ∗ On behalf of the Cochrane Adverse Effects Methods Group
    Affiliations
    University of Alberta, Canada
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  • Author Footnotes
    ∗ On behalf of the Cochrane Adverse Effects Methods Group
      To the Editor:
      We read with interest the report of the well-performed study of Avni et al
      • Avni T.
      • Bieber A.
      • Grossman A.
      • Green H.
      • Leibovici L.
      • Gafter-Gvili A.
      The safety of intravenous iron preparations: systematic review and meta-analysis.
      on the safety of intravenous (IV) iron administration published in the January 2015 issue of Mayo Clinic Proceedings. After carefully analyzing more than 100 published randomized, controlled trials (RCTs) that included more than 10,000 patients, the authors concluded that there is no increased risk of serious adverse effects (SAEs) with IV iron preparations compared with other oral iron preparations or placebo and that IV iron formulations are safe and may be given to iron-deficient individuals without fear of infection or cardiovascular events. Although the authors rightfully acknowledged in their discussion the substantial limitations of RCTs to detect rare SAEs, we think that several aspects of the studies included in the meta-analysis and postmarketing signals represent serious limitations to such a strong recommendation.
      First, as rightfully mentioned by the authors, risk of bias analysis found that allocation concealment was unclear in almost half of the trials and that only 18% of the assessed studies were double-blind trials. Also, most included trials (80%) did not specify how severity was defined. Although beyond the control of the authors, the fairly low quality of included studies could decrease the validity of their findings. Finally, for many relative risks for SAEs, confidence intervals were borderline, which could also be regarded as an additional limitation for their recommendation.
      Second, the authors did not take into account postmarketing signals coming from spontaneous reporting to pharmacoepidemiology surveillance programs. This factor was not the purpose of their research and thus is fully understandable. However, many cases of SAEs including anaphylaxis and death were reported to several national pharmacoepidemiology surveillance programs. After a careful reevaluation of the risks and benefits of IV iron, the European Medicine Agency and the Agence Nationale du Médicament et des Produits de Santé in France drastically tightened the procedures for IV iron administration.

      European Medicines Agency. New recommendations to manage risk of allergic reactions with intravenous iron-containing medicines. European Medicines Agency website. http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2013/06/WC500144874.pdf. Published June 28, 2013. Accessed February 14, 2015.

      This change had immediate practical consequences for the prescribers and their patients.

      European Medicines Agency. Assessment report for: Iron containing intravenous (IV) medicinal products. European Medicines Agency website. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/IV_iron_31/WC500150771.pdf. Published September 13, 2013. Accessed February 14, 2015.

      Swissmedic (the official body responsible for collecting all postmarketing adverse effects reports in Switzerland) announced 239 severe reactions following carboxymaltose administration only between 2010 and 2013. There were 3 deaths, including 1 secondary to an anaphylactic reaction. Causality between IV iron administration and death was less evident for the other cases (one cerebral haemorrhage 3 weeks after iron administration and one fetal death). Furthermore, 185 anaphylactic reactions, including 21 cases of shock were reported.
      • Eyal E.
      • Munz T.
      • Schochat T.
      • Bill H.
      Traitement intraveineux de la carence en fer: risques encourus.
      For ferumoxytol, 3 SAEs and 1 death were reported.
      • Eyal E.
      • Munz T.
      • Schochat T.
      • Bill H.
      Traitement intraveineux de la carence en fer: risques encourus.
      Following several reports of SAEs including deaths following ferumoxytol administration, Health Canada endorsed important new safety information on ferumoxytol in November 2014.

      FERAHEME (ferumoxytol)—important changes to the delivery and new restrictions on the use due to information on serious allergic reactions—for health professionals. Healthy Canadians website. http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2014/42607a-eng.php. Published November 21, 2014. Accessed February 18, 2015.

      One of the goals of postmarketing reporting is to capture SAEs that are too rare to be observed in RCTs or are only apparent when the drug in question is administered to other populations with different characteristics, such as children, pregnant women, or elderly people. The same applies for severe drug interactions (and potential SAEs), which are rarely captured in RCTs in which coadministration of other drugs is much rarer than in real life. Between 2002 and 2011, 19 such drugs were withdrawn from the market after pharmacoepidemiological studies signaled SAEs.
      • McNaughton R.
      • Huet G.
      • Shakir S.
      An investigation into drug products withdrawn from the EU market between 2002 and 2011 for safety reasons and the evidence used to support the decision making.
      In summary, the analysis of Avni et al
      • Avni T.
      • Bieber A.
      • Grossman A.
      • Green H.
      • Leibovici L.
      • Gafter-Gvili A.
      The safety of intravenous iron preparations: systematic review and meta-analysis.
      is correct. All IV iron formulations remain effective drugs. However, in view of their findings and of the current postmarketing signals, their conclusions should be somewhat more nuanced. Serious infusion reactions are reported more often with IV iron preparations, either in RCTs or in postmarketing surveillance programs, and this issue should not be forgotten. Prescribers should continue to use intravenous iron cautiously, as has already been recommended.

      European Medicines Agency. New recommendations to manage risk of allergic reactions with intravenous iron-containing medicines. European Medicines Agency website. http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2013/06/WC500144874.pdf. Published June 28, 2013. Accessed February 14, 2015.

      European Medicines Agency. Assessment report for: Iron containing intravenous (IV) medicinal products. European Medicines Agency website. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/IV_iron_31/WC500150771.pdf. Published September 13, 2013. Accessed February 14, 2015.

      FERAHEME (ferumoxytol)—important changes to the delivery and new restrictions on the use due to information on serious allergic reactions—for health professionals. Healthy Canadians website. http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2014/42607a-eng.php. Published November 21, 2014. Accessed February 18, 2015.

      References

        • Avni T.
        • Bieber A.
        • Grossman A.
        • Green H.
        • Leibovici L.
        • Gafter-Gvili A.
        The safety of intravenous iron preparations: systematic review and meta-analysis.
        Mayo Clin Proc. 2015; 90: 12-23
      1. European Medicines Agency. New recommendations to manage risk of allergic reactions with intravenous iron-containing medicines. European Medicines Agency website. http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2013/06/WC500144874.pdf. Published June 28, 2013. Accessed February 14, 2015.

      2. European Medicines Agency. Assessment report for: Iron containing intravenous (IV) medicinal products. European Medicines Agency website. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/IV_iron_31/WC500150771.pdf. Published September 13, 2013. Accessed February 14, 2015.

        • Eyal E.
        • Munz T.
        • Schochat T.
        • Bill H.
        Traitement intraveineux de la carence en fer: risques encourus.
        SwissMedic Vigilance News. 2013; 11: 6-7
      3. FERAHEME (ferumoxytol)—important changes to the delivery and new restrictions on the use due to information on serious allergic reactions—for health professionals. Healthy Canadians website. http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2014/42607a-eng.php. Published November 21, 2014. Accessed February 18, 2015.

        • McNaughton R.
        • Huet G.
        • Shakir S.
        An investigation into drug products withdrawn from the EU market between 2002 and 2011 for safety reasons and the evidence used to support the decision making.
        BMJ Open. 2014; 4: e004221

      Linked Article

      • The Safety of Intravenous Iron Preparations: Systematic Review and Meta-analysis
        Mayo Clinic ProceedingsVol. 90Issue 1
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          To amass all available evidence regarding the safety of intravenous (IV) iron preparations to provide a true balance of efficacy and safety.
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      • In reply—Continued Caution Recommended in Use of Intravenous Iron Preparations
        Mayo Clinic ProceedingsVol. 90Issue 5
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          We thank Dr Cachat and colleagues for their interest in our article and for the valuable information they are reporting. We tried to conduct an unbiased systematic review, but we are aware of the shortcomings of using published results of randomized, controlled trials (RCTs) to report severe adverse events: severe events are too rare to be captured by RCTs (this is why we included all trials on intravenous iron), recording of adverse events might be less rigorous and more biased than that of the primary outcome in such studies, the patients included in RCTs might not be representative of the patients given the drug in clinical practice, and for some medications, the time frame for identifying the adverse events might be the wrong one.
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